title: Effects of vercirnon on the activity of CYP3A4, CYP2C19 and CYP2C8 enzymes and BCRP and OATP1B1 transporters using probe substrates.
abstract: OBJECTIVE
  Vercirnon is a CCR9 chemokine receptor antagonist being developed for the treatment of Crohn's disease. As a variety of concomitant medications are often required for the treatment of Crohn's disease, it is important to characterise the drug interaction profile of vercirnon. To confirm the results of previous in vitro inhibition studies, this study assessed the in vivo effect of vercirnon on the activity of cytochrome P450 enzymes (CYP3A4, CYP2C19 and CYP2C8) and drug transport proteins (BCRP and OATP1B1) using probe substrates.
  
  
  METHODS
  This was an open-label, single-sequence, repeat-dose study conducted in 24 healthy adult subjects. On days 1-4, subjects received probe substrates (midazolam, pioglitazone, omeprazole and rosuvastatin; in that order), followed by administration of vercirnon 500 mg twice daily (BID) on days 5-14. On days 11-14, in addition to vercirnon 500 mg BID, subjects also received probe substrates as on days 1-4. Blood samples were collected for pharmacokinetic analysis of probe substrates, vercirnon and two of its metabolites.
  
  
  RESULTS
  Geometric least-squares mean ratios (90 % confidence interval) of area under the concentration-time curve from time zero to infinity for probe administered with vercirnon (test) compared with probe alone (reference) for midazolam, pioglitazone, omeprazole and rosuvastatin were 0.92 (0.85, 0.99), 1.01 (0.95, 1.07), 0.99 (0.76,1.31) and 0.98 (0.88, 1.09), respectively.
  
  
  CONCLUSIONS
  Co-administration of probe substrates midazolam, pioglitazone, omeprazole, and rosuvastatin following repeat dosing of vercirnon 500 mg BID demonstrated vercirnon had no clinically significant effect on CYP3A4, CYP2C8, CYP2C19 enzyme activity or BCRP or OATP1B1 transporter activity.
authors.affiliation: Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC, 27709, USA, Lynda.J.Haberer@gsk.com.
authors.forename: Lynda J
authors.initials: LJ
authors.lastname: Haberer
authors.forename: Iain
authors.initials: I
authors.lastname: McSherry
authors.forename: Anna
authors.initials: A
authors.lastname: Cargill
authors.forename: Linda
authors.initials: L
authors.lastname: McCarthy
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D027361:Organic Anion Transporters / Q000378:metabolism*; D000077205:Pioglitazone; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics; D054388:Receptors, CCR / Q000037:antagonists & inhibitors; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D045162:Thiazolidinediones / Q000097:blood / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C119309:CC chemokine receptor 9; C583420:CCX282-B; D005464:Fluorobenzenes; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D011743:Pyrimidines; D054388:Receptors, CCR; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D045162:Thiazolidinediones; D000068718:Rosuvastatin Calcium; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C450259:CYP2C8 protein, human; D065731:Cytochrome P-450 CYP2C19; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D008874:Midazolam; D000077205:Pioglitazone